Theophylline derivatives



Unite rates THEOPHYLLINE DERIVATIVES Norman H. Leake and Marvel L. Fielden, Bristol, Tenn., 7 assignors to The S. E. Massengill Company, Bristol, Tenn., a corporation of Tennessee No Drawing. Application March 3, 1959 Serial No. 796,774

20 Claims. (Cl. 260-253) This invention relates to new compounds which are derivatives of theophylline or 1,3-dimethyl xanthine.

This application is a continuation-in-part of Leake and Fielden applications Serial Numbers 618,711 and 618,672, both filed October 29, 1956, both now abandoned.

The object of this invention is to provide novel 7- and S-substituted theophylline derivatives.

Another object is to provide new 7-subst'ituted 8-dialkylaminoalkylamino theophylline derivatives, which are characterized by marked therapeutic activity.

Still another object is to provide novel 7-substituted 8- halotheophylline derivatives, which can be employed in the preparation of more complex theophylline derivatives, such as said 7-substituted S-dialkylaminoalkyl theophylline derivatives.

Other objects and advantages of our invention will become obvious from the following detailed description.

The new compounds of our invention are characterized by the following structural formulae:

2,928,833 Eatented Mar. 15, 1960 and soluble, in hot organic solvents such as glacial acetic acid and isopropanol. y

We can prepare the free base compounds of group II by reacting an 8-halotheophylline of group I having the desired 7-substituent with the appropriate di(lower-alkyl)-. amino-(lower-alkyl)-amine. The free base 8-dialkylaminoalkylamino compounds are generally water-insoluble and vary from oils to crystalline solids at ordinary temperatures. Theyv form salts, both with inorganic acids, such as HCl, HBr, H 80; and I-INO and with or-. ganic acids, such as acetic, propionic, maleic, fumaric, tartaric, citric, benzoic and salicyclic acid, which generally are crystalline solids of higher melting point than the parent free base and of increased water solubility. The physical characteristics of many of the acid salts in terms of their higher melting points and superior water solubility make them highly advantageous for use in many instances where these characteristics are desirable. The acid salts can be prepared by addition of the acid to a solution of the free base parent compound.

The quaternary ammonium derivatives of the 8dialkylaminoalkylamino compounds can be made by treating a solution of the free base parent compound with an organic sulfate, nitrate or halide such as the chloride, bromide or iodide, and the like. The quaternary ammonium derivatives are generally advantageous because of their higher melting, crystalline solid properties and their sub stantial water solubility.

EXAMPLE I EXAMPLE II 7-propargyl-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.1 molar quantities of 8-chloro-theophylline and propargyl bromide and refluxing for 2 hours.

The compound melted at 166-8 C.

EXAMPLE IH 7 (2,3-epoxypropyl) -8 chloro-theophylline was pre- H pared substantially as described in Example I, employing wherein hal is halogen, such as chlorine, bromine andprepared by reacting an 8-halo-theophylline with the i halide of the compound which is to be introduced as the 7-sub'stituent in the presence of an alkali such as NaOH or KOH. The compounds are whitecrystalline solids which are insoluble in water, dilute acid and dilute I 0.2 molar quantities of epichlorohydrin and 8-chloro-. theophylline and refluxing for 7 hours. The product melted at 215-20 C.

EXAMPLE IV 7-cyclohexyl-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.25 molar quantities of cyclohexyl chloride and 8-chloro-theophyl line and refluxing for 24 hours.

EXAMPLE V 7-benzyl-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.2 molar quantities of benzyl chloride and 8-chloro-theophylline and refluxing for 5 hours. The product melted at 149- 50 C.

EXAMPLE VI 7-p-methylbenzyl-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.125 molar quantities of p-methylbenzyl bromide and 8-chloro-. theophylline and refluxing for 4 hours. The product melted at 163-5 C. in

.3 EXAMPLE vn kaessresa 7-m-methy1benzyl-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.125 7 molar quantities of m-methylbenzyl bromide and 8-chloro-theophylline and refluxing for 4 hours. The product melted at 123-5 C.

. EXAMPLE 7-o-methy1benzy1-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.1 molar quantities of o-methylbenzyl bromide and 8-chlorotheophylline and refluxing for 2 /2 hours. The'pro'duct melted at 158-.60 C.

EXAMPLE 1x .7rp-.nitrobenzyl-8rchloro-theophylline was prepared substantially as .de'scribedin Example vLernployingOJ snolar quantities of pgnitrobenzyl bromide and -.8-chloro-theophylline and refluxing .for 3 hours. The product melted 'at 2-l517 C.

EXAMPLE X S-chloro-theophylline and m-nitrobenzyl chloride in 0.056 molar quantities were heated with 0.038 N'KOH solution in 50% aqueous ethanol at 125"? C. in a closed shaker reaction vessel for 24 hours. The cooled reaction mixture was extracted several times with chloroform which was then evaporated. The "product was digested with isopropanol, filtered, dried and recrystallized. The 7-m-nitrobenzyl-8 chloro-theophylline melted at 183-7" EXAMPLE X1 7-(3,4-dichlorobenzyl)8 ch1oro-theophylline was prepared substantially as described in Example I, employing 0.2 molar quantities of '3,4-dichlorobenzylchloride and'8- chlorotheophylline and refluxing for 3 /2 hours.

EXAMPLE XII 7-(2,4-dichlorobenzyl)-3-chloro-theophylline was prepared substantially as described in Example X, employing 0.056 molar quantities of 2,4-dichlorobenzyl chloride and heating for 24 hours.

at 207-10.C.

EXAMPLE XIII 7-a-rnethylbenzyl-S-chloro-theophylline was prepared substantially as described in Example I, employing 0.125 molar quantities of u-methylbenzyl bromide and 8-c'hlo ro-theophylline and refluxing for 3 hours.

EXAMPLE XIV 7 fl-phenylethyl 8-chloro-theophylline was prepared substantially as described in'Exampl'eI, employing 0.1 molanquantities of fi-phenylethyl bromide and 8-chlorotheophylline and refluxing for 2 hours. Theproduct melted at l48-5l C.

EXAMPLE XV 7-,S-cyclohexylethyl-S-chloro-theopihylline was prepared substantially as described in Example I, employing10.25 molar quantities of B-cyclohexylethyl bromide and -8- chloro-theophylline and refluxingfor 3 hours.

EXAMPLE XVI "7 phenacyl-8chloro-theophylline was prepared .rsub 'stantially "as described in Example I. employing, 0.25 molar quantities of :phenacyl bromide and 8-.chloro-theophylline and refluxing for 4'hours. The compound .-melted at 245-7 C. i

EXAMPLE XVII 7*p-nitrophenacyl-8'chloro-theophylline was prepared substantially as described in Example X, .usirlg"0.'056 molar quantities of p-nitrophenacyl bromide aiid'SrchJo: ro-th'eophylline and heating for '24 hours. .Ihe' "product melted at 203-5 C.

4 EXAMPLE XVIII 7-v-phenyl-propyl-8-chloro-theophy1line was prepared substantially as described in Example'l, employing 0.2 molar quantities of 'y-phenyl-propyl chloride and 8-chloro-theophylline and refluxing for 5 hours.

. EXAMPLE XIX 7-,B-phenoxyethyl-8-chloro-theophylline was prepared substantially as described in Example I, employing 0.25 molar quantities of fi-phenoxyethyl chloride and 8-ohloro-theophylline and refluxing for 24hours.

' EXAMPLE 7-propargyl-8abromo-theophylline was prepared substantially as described in Example I, employing 13 grams (0.05 mol.) of 8-bromo-theophylline, 7.2 grams (0.06

mol.) of propargyl bromide and 50 ml. 1N NaOI-I. The

' product jmelted at 189-91 C.

I treated with ethereal hydrogen chloride.

The compound melted EXAMPLE XXI 7-benzyl-8-bromo:theophylline was prepared substantially-as described in Example I, employing 13 grams (0.05 mol) of 8-bromo-theophylline, 7.6 grams (0.06 mol.) of benzyl chloride and 5 ml. 1N NaOH. The product melted at l7 C.

EXAMPLE XXII A :mixture of 12.7 grams of 7-allyl-8-chloro-theophyl-.

7 propargyl 8 p diethylarninoethylamino theo: phylline was prepared according to the method described in Example XXII, employing 8.4 grams of 7-propargyh S-chloro-theophylline and 7.8 grams of fi-diethylaminoethylamine. Refluxing time was 17 hours. The compound is a white, crystalline solid having a melting point of l29-3l C.

7 propargyl 8 S diethylaminoethylamino theophylline hydrochloride was prepared by treating an other solution of the free base with ethereal HCl. The salt is a crystalline solid .having a melting point of 245 C.

EXAMPLE XXIV '7 benzyl 8 y --'dimethylaminopropylamino theophylline was prepared according "t0 the method described in Example XXII, employing 15.3 grams of 7- benzyl-S-Chlorodheophylline and 10.2 grams of 'y-dimethylaminopropylamine. Refluxing time was 21 hours.

'The' freebase compound is an oil at ordinary tempera-l tures.

7 benzyl 8 'y dimethylaminopropylamino theophylline dihydrochloride was prepared by treating an isopropanol solution of the free base with ethereal. I-lCl. The salt is a crystallinesolid'having'a melting point of ZOO-205 C.

' EXAMPLE XXV benzyl -f8 1 ddiethylaminoethylamino theophylline was'jprepared "according to the method described in Example TXXII, using grams of"7-bc. ,yl-8 -chloro theophylline "and -11.6 grams of B=diethy1aminoethyl i amine. Refluxing time was 12 hours. The free base compound is an oil at ordinary temperatures.

7 benzyl 8 ,6 diethylaminoethylamino theophylline hydrochloride was prepared by treating an ethanol solution of the free base with ethereal HCl. The salt is a crystalline solid melting at 208-9" C.

EXAMPLE XXVI 7 p nitrobenzyl 8 3 diethylaminoethyl-amino theophylline was prepared according to the method described in Example XXII, employing 17.5 grams of 7- p-nitrobenzyl-8-chl0ro-theophylline and 11.6 grams of diethylaminoethylamine. Refiuxing time was 17 hours. The free base compound is an oil at ordinary temperatures.

7 p nitrobenzyl 8 B diethylaminoethylamino theophylline hydrochloride was prepared by treating a benzene solution of the free base with ethereal HCl. The salt is a crystaline solid melting at 195 C.

EXAMPLE XXVII EXAMPLE XXVIII 7-(3,4-dichlorobenzyl)-8 3 diethylaminoethylaminotheophylline was prepared according to the method described in Example XXII, employing 11.2 grams of 7-(3,4- dichlorobenzyl)-8-chloro-theophylline and 7.0 grams of B-diethylaminoethylarnine. Refluxing time was 8 hours. Yield was 7.5 grams. The compound is a solid melting at 145-50" C.

7-(3,4-dichlorobenzyl)-8-fl diethylaminoethylaminotheophylline hydrochloride was prepared by treating an isopropanol solution of the free base with ethereal HCl. The salt is a crystalline solid melting at 195205 C.

EXAMPLE )QGX 7-phenacyl-8-fl-diethylaminoethylamino theophylline was prepared according to the method described in Example XXII, employing 16.6 grams of 7-phenacyl-8- chloro-theophylline and 11.6 grams of fi-diethylaminoethylamine. Refiuxing time was 5 hours. Yield was 11.5 grams. The compound is a solid melting at 146-9 C.

7-phenacyl-8-B-diethylaminoethylamino theophylline hydrochloride was prepared by treating an isopropanol solution of the free base with ethereal HCl. The salt is a crystalline solid melting at 265 C.

EXAMPLE XXX 7-B-phenylethyl-8-fl-diethylaminoethylamino theophylline was prepared according to the method described in Example XXII, employing 15.9 grams of 7-fl-phenylethyl- 8-chloro-theophylline and 11.6 grams fi-diethylaminoethylamine. Refiuxing time was 19 hours. The compound is a solid melting at 132-3 C.

7-B-phenylethyl-8-/3-diethylaminoethylamino theophylline hydrochloride was prepared by treating an ethanol solution of the free base with ethereal HCl. The salt is a crystalline solid melting at 225-8 C.

EXAMPLE XXXI 7-propargyl- 8-,8 -diethylaminoethylamino theophylline fumaraterwas prepared by adding fumaric -acid to an w aseethanol solution of the free base parent compound. The

fumarate salt isa white crystalline solid having a melting point of 1913 C.

' EXAMPLE XXXII- 8 fl-diethylaminoethylamino-7-propargly theophylline and propargly bromide in ethanol solution were heated The quaternary am-y under reflux for several hours.

monium product, 8-(5-diethylproparglyamino)-ethylamino-7-propargyl-theophylline bromide melts at 201-;

204 C. with decomposition.

EXAMPLE Z O(X III The quaternary ammonium derivative 8-(B-diethylbenzyl-amino)-ethylamino-7-propargyl-theophylline chloride was prepared as described in Example XXXII from 8- 3-diethylaminoethylamino-7-propargyl-theophylline and benzyl chloride. The compound melts at 1523 C. with decomposition.

EXAMPLE XXXIV The quaternary ammonium derivative 8-;8-(d-iethylmethylamino)-ethylamino-7-propargly-theophylline bromide was prepared by treating an ethanol solution of 8- B diethylaminoethylamino-7-propargyltheophylline with methyl bromide in a closed system at 80 C. for several hours. The compound has a melting point of 22 3-5 C.

EXAMPLE XXXV 7-cyclohexyl-8- 8-diethylaminoethylamino theophylline was prepared substantially as described in Example XXII by refluxing 14.8 grams 7-cyclohexyl-8-chloro-theophylline with 11.6 grams ;8-diethylaminoethylamine in ethanol solution in a closed system for about 8 hours at a temperature of about C.

EXAMPLE XXXVI S-(fl diethylaminoethylamino) -7-( 2,3 epoxypropyl)-,

theophylline hydrochloride was prepared as follows. 13.5 grams of 7-(2,3-epoxypropyl)-8-chlorotheophylline, 11.6 grams of B-diethylaminoethylamino and 300 ml. of water were heated at reflux for 20 hours. At the end of this time, an oil was precipitated by saturating the cooled solution with NaCl and warming. The supernatant was decanted and the oil dissolved in isopropanol. This solution was dried azeotropically by boiling out benzene. Addition of ethereal hydrogen chloride caused a hydroscopic solid to separate, which after recrystallization from isopropanol yielded 3.5 grams of a white crystalline solid melting at 265-75 C. with decomposition.

' EXAMPLE XXXVI I The quaternary ammonium derivative 7-allyl-8(,6-diethylaminoethylamino)-theophylline allyl bromide, was s prepared as follows. Two grams of 7-allyl-8(,6-diethylarninoethylamino)-theophylline (0.006 mole) were dis-' solved in anhydrous isopropanol. 1 gram of allyl bromide (0.066 mole) was added and the mixture heated at reflux 6 hours. The product was precipitated by adding anhydrous ether. The resulting white solid was filtered and dried; wgt, 1.4 gm., M.P. -200 C.

The 8-dialkylaminoalkylamino compoundsof our invention are therapeutically active, for example, as antihistamines, as diuretics, and in reducing arterial blood pressure.

EXAMPLE XXXVIII To determine antihistaminic activity, rats or guinea pigs were treated with the drug intravenously or intraperitoneally, and then challenged with histamine-diphosphate intravenously at 0.4 mg./kg. Active compounds prevent the normal blood pressure lowering response to histamine anddeathff 1 i I spasms EXAMPLE XXXIX 7=benzyl 8fi-diethylaminoethylamino-theophylline HCl possessesmarked blood pressureloweringactivity as'indicated by-thefollowingtest data:

(A) At a dose of- S mg.'/kg intravenously, in 6 dogs, the compound caused an average decrease-of 50% in blood pressure, from 120 to 60 mm. Hg.

(B) Arterial bloodpressure in unanesthetized trained rats was measured by observing the pressure at which there was an increase in volume of the tail as the pres.- sure ina restrictingcutfwas lowered. At a-does of 15 mg./kg., intraperitoneally, twice a daytor thirty days,

an averagedecrease was observed of 30%belownormal...

from about 100 to 70 mm. Hg.

EXAMPLE XL 7 allylt 8*- ,8-- diethylaminoethylamino-theophylline. possesses marked 'blood pressure lowering activity asindicated by the following test data.

The carotid artery of a 2.25 kg. catwas-cannulated and connected to an ink writing mercury manometer. The compound, at mg./kg., was injected via the saphenous vein.- Blood, pressure was reduced from 120 to 60, returned to 100-within 4 minutes, and remained at this level for 1 hour.

EXAMPLE XLI 7 allyl- 8 B diethylaminoethylamino-theophylline.- possesses marked diuretic activity and is comparable in" this ;respect to :aminophylline.

Rats:weighing- 200-300 grams were fasted for 18-24:- hoursand given physiological saline (0.9%) at a dose of cc./kg. body weight Thedrugs weredissolved in the saline and givenat-the'doses shown in the table. The amount of urine produced in five hours was measured. Aminophylline was used asst-standard. Saline controls (no drugs) were-also run;

Fromthetableit is seen that with-no drug, about- 55%.? of the-watergiven as saline wasreturned-"as uri-ne.- Percent return indicates the-amount of-urine ex pressed-asapercentageof the normal saline admin istered' to the rats. The collection period was five hours: With aminophylline, the percent return was about 80' at 40 rug/kg. and 125 at 80 rug/kg. .The-7-allyl'compound was comparable inactivity to'aminophylline;

Aminophylline, 7-Allyl-8-DEAEA Saline, percent return; Theophylline, percent percent mg./kg. return, rug/kg. return Toxicity of the-compounds is relativelylow aszshowniu by the acute LD data given in the following tabie;

a (B Table l Compound LDzq, Anirnal. Route mgJkg.

7-Allyl-8-fl-diethy1aminoethy1an1ino- 30 rats LV.

theophylline, H01. 7 -Propargy1-8-B-diethylaminoethylrats LV.

theophylline. H01. 7 Benzyl 8 -6 diethylaminoethyl 35 rats LV.

amino-theophylline, H01.

Do 100 mice LP. 7 -o-l\Iethy1benzyl-8-fi-diethylamino- 50 rats LV.

ethylamino-theophylline, H01.

Do 30 guineapigs. I.V. 7-Phenaeyl-8-B-diethylaminoethy1- 100 rats LV.

amino-theophylline, H01.

' 7 EXAMPLE XLII Rats-given 20 mg./kg. daily, intraperitoneally of 7- benzyl 8 3 diethylaminoethylamino-theophylline for one year showed no adverse effects upon appetite, growth, reproduction and appearance. No abnormalities were found upon autopsy of sacrificed animals.

The 8-dialkylaminoalkylamino compounds can be administered in any desired manner. Where an aqueous a vehicle is to be used, it is, of course, desirable to employ the more water-soluble derivatives, namely the acid salts orquaternary ammonium derivatives. The compounds can also be carried in solution in an organic solvent, such as ethanol, or in admixture with a suitable non-toxic, solid vehicle, such as starch, milk sugar,

entonite and the like.

Although this invention has been described with reference to illustrative embodiments thereof, it will be apparentto those skilled in the art that the principles offthis invention may be embodied in other forms but within the scope of the claims.

We claim:

1. Compounds selected from the group consistingof wherein Ais lower alkylene; All: is lower. alkyl; and. R

is selected ;from the group consisting of lower-alkenyl,

lower-alkinyl, epoxy- (lower-alkyl) phenyl-(lower-alkyl) halophenyl-(lower-alkyl), (lower-,alkyl)-phenyl-(lower alkylL.nitrophenyl-(lowenalkyl), cyclohexyl, and hen-- zoyl-(lower-alkyl); their acid salts; and their quaternary wherein; fldsxlower alkylene; *Al-k .is lower-alkyl; and .R 7

is phenyl-(lower-alkyl)? 3. The acid salts of the compounds of claim 2. 4. Compounds having the structural formula:

wherein A is lower-alkylene; Alk is lower alkyl; and R is (lower-alkyl)-phenyl-(lower-alkyl).

5. The acid salts of the compounds of claim 4.

6. The acid salts of 7-benzyl-8-fi-diethylaminoethylamino-theophylline.

7. The HCl salts of 7-benzyl-S-B-diethylaminoethylamino-theophylline.

8. The acid salts of 7-o-methylbenzy1-8-B-diethylaminoethylamino-theophylline.

9. The HCl salt of 7-o-methylbenzyl-S-B-diethylaminoethylamino-theophylline.

10. Compounds having the structural formula:

wherein A is lower-alkylene; Alk is lower-alkyl; and R is lower-alkenyl.

10 11. 7 allyl 8 3 diethylaminoethylamino'theophyiline.

12. The HCl salt of 7 allyl 8 5 diethylaminoethylamino-theophylline.

13. Compounds having the structural formula:

(lower-alkyl).

16. The compounds of claim 13 in which R is (loweraIkyD-phenyl (lower-alkyl).

17. The compounds of claim 13 in which R is loweralkenyl.

18. 7-benzyl-8-chloro-theophylline.

19. 7-o-methylbenzyl-8-chloro-theophy1line.

20. 7-allyl-8-chloro-theophylline.

No references cited. 

1. COMPOUNDS SELECTED FROM THE GROUP CONSISTING OF THE COMPOUNDS HAVING THE STRUCTURAL FORMULA: 